Geometric and topological control of organogenesis (360G-Wellcome-307664_Z_23_Z)

Building functional organs is critical for organismal growth and life, and thus organogenesis is a remarkably robust process. Yet, our understanding of how a developing organ acquires its characteristic form suited for its functionality remains rudimentary. To address this long-standing question, we will use a highly tractable model system, the developing zebrafish heart. As the embryo grows, the primitive myocardial wall of the zebrafish heart transforms from a monolayer epithelium into a complex 3D meshwork, which is critical for heart function. Yet, the mechanisms driving these crucial intricate topological transitions remain elusive. Thus, integrating quantitative imaging, biophysics, transcriptomics and theoretical modelling, we will uncover how form and function of a vital organ, the heart, emerge reproducibly during development. We will elucidate – 1) how geometry confines cellular processes locally to pattern the myocardial tissue, and if this entails localized extracellular matrix remodelling and altered fluid mechanics, 2) how ventricular meshwork architecture, called trabeculae, are shaped, constrained, and canalized during development and perturbations, and how this affects heart function, and 3) mechanisms underlying atrial meshwork morphogenesis. These findings will reveal fundamental design principles underlying robust organogenesis, yield a rational framework for tissue engineering efforts and improve our understanding of cardiac malformations.